CN112759562B - Preparation method of high-purity hydrobromic acid vortioxetine - Google Patents
Preparation method of high-purity hydrobromic acid vortioxetine Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
The invention belongs to the field of chemistry, and particularly relates to a preparation method of high-purity vortioxetine hydrobromide. The invention provides a preparation method of vortioxetine hydrobromide with high purity, which uses o-fluoronitrobenzene and piperazine as starting materials to further prepare the vortioxetine hydrobromide in an organic solvent.
Description
The technical field is as follows:
the invention belongs to the field of chemistry, and particularly relates to a preparation method of high-purity vortioxetine hydrobromide.
Background art:
vortioxetine is a novel antidepressant drug jointly developed by Danish Lingbei pharmaceutical company and Japan Wutian pharmaceutical company, and is approved by FDA to be on the market for treating adult major depression within 9 months and 30 days in 2013, and is sold under the trade name Brintellix; 11/21/2017, which was approved for marketing in china. The chemical structural formula is as follows:
the medicine can inhibit serotonin reuptake, and has effects of 5-HT1A receptor agonist, 5-HT1B receptor partial agonist, and 5-HT1D and 5-HT7 receptor antagonist. The diversity of actions of this drug allows its neurotransmission in several systems to produce a modulation, primarily of serotonin, presumably also norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. Vortioxetine is the first antidepressant with multiple pharmacodynamic activities.
Many reports are made at home and abroad about the preparation method of vortioxetine. Through literature search and patent analysis, vortioxetine can be prepared from the following compounds in class 7. Wherein the compounds 1,4, 5, 6 and 7 can be used for preparing the vortioxetine by reduction, and the compounds 2 and 3 are respectively used for preparing the vortioxetine by coupling.
The method for preparing the vortioxetine from the compound 3 mainly comprises the following steps:
the method comprises the following steps: patent WO2017216805 discloses a preparation method of vortioxetine, which comprises the following steps
The main problems of the method are as follows: 1. the reaction yield is low, the preparation cost of the product is increased by 2, the debenzylation reaction has more side reactions, and the subsequent purification difficulty is increased, so that the total yield is reduced, and the preparation cost is increased.
The method 2 comprises the following steps: chinese patent CN105017175 discloses a preparation method of vortioxetine, namely compound 3b is used as a starting material, and the preparation method of the vortioxetine hydrobromide is used for preparing the vortioxetine through diazotization, iodination reaction, coupling reaction, deacetylation and salification.
The main problems of the method are as follows: 1. as can be seen from the fact that the yield of the hydrobromide prepared in the last step was only 53.5%, more side reactions occurred in the deacetylation reaction. This inevitably increases the difficulty of subsequent purification, which also reduces the overall yield and increases the preparation cost. 2. The purity of the vortioxetine hydrobromide prepared by this method is not specified.
The method 3 comprises the following steps: patent WO2015169130 discloses a method for preparing vortioxetine, which comprises the steps of taking 3C as a starting material, performing coupling reaction, and removing protecting groups to obtain vortioxetine. The method is similar to the method 2 in that,
wherein R represents acetyl, 9 fluorenylmethyloxycarbonyl, benzyloxycarbonyl or trifluoroacetyl, and X is halogen
The main problems of the method are as follows: the first coupling reaction requires tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) And bis (2-diphenylphosphinophenyl) ether are used as catalysts, so that the price is high, the catalyst cannot be recycled, and the preparation cost is increased;
the removal of the amino protecting group used in the above three methods is accompanied by many side reactions. This inevitably increases the difficulty of subsequent purification, which also reduces the overall yield and increases the preparation cost.
In addition, patents WO2013/102573 and CN10472906 report a synthesis method of vortioxetine, that is, piperazine, 2, 4-dimethyl iodobenzene and 2-bromophenylthiol are used as starting materials, toluene is used as a solvent, sodium tert-butoxide is used as an alkali, bis (dibenzylideneacetone) palladium and binaphthyl diphenylphosphine are used as catalysts, and the vortioxetine is obtained by a one-pot reaction under the protection of nitrogen;
the method has the main problems that: the starting materials are expensive and difficult to obtain; the use of heavy metal catalysts is expensive and cannot be recycled; the one-pot reaction has inevitable by-products and more impurities; increasing the difficulty of purification.
By combining the above routes, expensive palladium catalyst and phosphine ligand are used in the synthesis method, the reaction conditions are harsh, and the industrial production is not facilitated; or more side reactions are generated when the amino protecting group is removed, so that the purification difficulty is increased, the preparation cost is increased, and the industrial production is not facilitated.
The invention content is as follows:
the invention aims to solve the problems of low purity, high cost and the like of the vortioxetine prepared in the prior art, and provides a preparation method for preparing the vortioxetine hydrobromide with high purity.
The invention is realized by the following technical scheme:
a preparation method of high-purity vortioxetine hydrobromide is characterized by comprising the following steps:
step 1, reacting o-fluoronitrobenzene and piperazine in an organic solvent at a certain temperature to obtain a compound FLXT-1; the reaction formula is as follows:
step 2, FLXT-1, sulfonyl chloride and an alkaline compound react in an organic solvent at a certain temperature, and a compound FLXT-2 is obtained after post-treatment;
step 3, dissolving the compound FLXT-2 in an organic solvent, and reducing under the action of a reducing agent or carrying out hydrogenation reduction by using iron powder or palladium carbon as a carrier to obtain FLXT-3;
step 4, dissolving the compound FLXT-3 by using a solvent, adding acid, cooling to-10-5 ℃, and dropwise adding a diazotization reagent aqueous solution for reaction to prepare a compound FLXT-4;
step 5, heating a compound FLXT-4, 2,4 dimethyl thiophenol, iodinated ketone and a basic compound in an organic solvent to 80-180 ℃ for reaction, and performing aftertreatment to obtain FLXT-5;
and step 6, mixing the compound FLXT-5 with a phenolic compound and a 30% hydrobromic acid acetic acid solution, reacting at a certain temperature, and performing aftertreatment to obtain high-purity Vortioxetine hydrobromide, wherein the reaction formula is as follows:
LG is mesyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl or o-nitrobenzenesulfonyl.
Further, in the step 1, the feeding molar ratio of the o-fluoronitrobenzene to the piperazine is 1: 3.0-8.0.
In the step 2, the sulfonyl chloride is methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride or o-nitrobenzenesulfonyl chloride. The molar ratio of FLXT-1 to sulfonyl chloride to basic compound is 1: 1.0-3.0: 1.0 to 3.0; the alkaline compound is triethylamine, pyridine, N-diisopropylethylamine potassium carbonate and the like, preferably triethylamine; the organic solvent is dichloromethane, toluene, tetrahydrofuran and the like, preferably dichloromethane; the certain temperature in the step 2 is 0-40 ℃, and preferably 10-30 ℃.
In the step 3, the reducing agent is hydrazine hydrate, iron, tin, sodium hydrosulfite and hydrogen, preferably hydrazine hydrate.
In the step 4, the acid is p-toluenesulfonic acid, sulfuric acid, hydrochloric acid or trifluoroacetic acid and the like; preferably sulfuric acid; the diazotization reagent is sodium nitrite and potassium nitrite; preferably sodium nitrite; the iodine reagent is potassium iodide, sodium iodide or methylidene iodide, preferably potassium iodide.
In the step 5, the alkaline compound is sodium carbonate, potassium hydroxide or sodium hydroxide, and the like, preferably potassium hydroxide; the organic solvent is selected from one or any combination of the following: 1,4 dioxane, N-dimethylformamide or dimethyl sulfoxide, preferably 1,4 dioxane; the feeding molar ratio of FLXT-4 to 2, 4-dimethyl thiophenol, iodinated ketone and basic compound is 1.0: 1.1-3.0: 0.02-0.31: 1.5:5.0, preferably 1.0: 1.2-1.8: 0.05-0.10: 1.9 to 2.5.
In the step 6, the phenolic compound is p-methylphenol, p-methoxyphenol, phenol or p-diphenol, preferably p-methylphenol, p-methoxyphenol or phenol, more preferably p-methylphenol; the certain temperature is 20-90 ℃, preferably 50-75 ℃, and more preferably 60-70 ℃. The feeding molar ratio of the compound FLXT-5 to the phenolic compound and the hydrobromic acid is 1.0: 1.0-5.0: 3.0: -20.0, preferably 1.0: 1.5-3.0: 4.0 to 11.0, more preferably 1.0: 1.8-2.5: 5.0 to 8.0.
The reaction formula is as follows:
LG is methylsulfonyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl or o-nitrobenzenesulfonyl
The invention has the beneficial technical effects that: the invention provides a preparation method for preparing vortioxetine hydrobromide with high purity, which has the advantages of low price of raw materials, low cost, simple operation, high purity of prepared vortioxetine hydrobromide, less impurities and the like.
Examples
Step one, preparation of FLXT-1
Adding anhydrous piperazine (180.9g and ethanol (700ml) into a 2000ml reaction bottle, stirring at room temperature, slowly adding o-fluoronitrobenzene (98.8g) and ethanol (220ml) solution, reacting at room temperature for 7-8 hours after dropping, filtering when continuing to 2 hours, concentrating to obtain ethanol, adding dichloromethane (450ml) and water (400ml), extracting and separating, extracting the water phase with dichloromethane (200ml), combining the organic phases, washing with saturated saline solution, concentrating to obtain an oily substance, adding 450ml water into the concentrated oily substance, stirring, adding 80ml concentrated hydrochloric acid, adjusting the pH to 1-3, stirring at room temperature for 20 minutes, extracting and separating, adding NaOH into the water phase, adjusting the pH to 10-13, stirring at room temperature for 20 minutes, adding dichloromethane (300ml), extracting and separating, washing the water phase with dichloromethane (200ml x2), combining the organic phases, washing with saturated saline solution (500ml), the residue was dried over anhydrous magnesium sulfate and filtered to obtain 130.5g of a red oil, which was obtained in 90% yield.
Step two, preparation of FLXT-2 FLXT-1(145g, 0.7mol), triethylamine (41.8g, 0.414mol) and dichloromethane (700ml) were added to a 2000ml reaction flask, and benzenesulfonyl chloride (136g, 0.77mol) was added dropwise under cooling in an ice salt bath (0-10 ℃). After dropping, the reaction was carried out at 10 ℃ for 1 hour. After the reaction was completed, 170g of an aqueous sodium hydroxide solution (30%) was slowly added thereto and stirred for 1 hour. Extraction, the aqueous phase being extracted with dichloromethane (200ml) and the combined organic phases being washed with 1% dilute hydrochloric acid (500ml), saturated sodium bicarbonate solution (500ml) and saturated brine (500ml), respectively; the mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain methylene chloride, until a large amount of solid was precipitated. Stirring was carried out at room temperature for 2 hours, filtered and dried at 60 ℃ to constant weight to give 226.1g of a yellow solid with a yield of 93.0%.
MS(m/z)：439.14[M+H]+
1H NMR(400MHZ，CDCl3，TMS)
δ：7.66-7.71(m，3H)，7.57-7.63(m，1H)，7.53-7.55(m，3H)，7.15-7.23(m，2H)，3.16-3.23(m，8H).
Step two, preparation of FLXT-2 FLXT-1(145g, 0.7mol), pyridine (32.75g, 0.414mol) and tetrahydrofuran (600ml) were added to a 2000ml reaction flask, and benzenesulfonyl chloride (136g, 0.77mol) was added dropwise under cooling with an ice salt bath (0-10 ℃). After dropping, the reaction was carried out at 30 ℃ for 1 hour. After the reaction was completed, 170g of an aqueous sodium hydroxide solution (30%) was slowly added thereto and stirred for 1 hour. Extraction, the aqueous phase was extracted with ethyl acetate (300ml), and the combined organic phases were washed with 1% dilute hydrochloric acid (500ml), saturated sodium bicarbonate solution (500ml) and saturated brine (500ml), respectively; the mixture was dried over anhydrous magnesium sulfate, filtered and concentrated to give tetrahydrofuran, until a large amount of solid precipitated. Stirring was carried out at room temperature for 2 hours, filtered and dried at 60 ℃ to constant weight to give 226.1g of a yellow solid with a yield of 93.0%.
Step three, preparation of FLXT-3
Adding FLXT-2(86.8g, 0.25mol) and ethanol (1000ml) into a 2000ml reaction bottle, adding activated carbon (14.4g) and ferric trichloride hexahydrate (10.8g), heating to 60-70 ℃, dropwise adding 80% hydrazine hydrate (156.5g) into the solution, and continuing to react for 2-3 hours after dropwise adding; after TLC monitoring reaction, cooling to 40 ℃, adding 400ml dichloromethane, filtering, and washing with dichloromethane; the dichloromethane and part of the ethanol were concentrated, cooled to 0-10 ℃ and stirred for 1 hour, filtered and dried to constant weight at 60 ℃ to give 75.5g of a white solid with a yield of 95.2%.
MS(m/z)：299.14[M+H]+
1H NMR(400MHZ，CDCl3，TMS)δ：7.86-7.88(m，2H)，7.62-7.69(m，3H)，6.98-7.01(m，2H)，6.74-6.81(m，2H)，3.88(br s，2H)，3.03-3.23(m，8H).
Step three, preparation of FLXT-3
Adding FLXT-2(86.8g, 0.25mol) and ethanol (2000ml) into a 5000ml high-pressure reaction kettle, adding palladium-carbon (8.6g), replacing for 3 times with nitrogen, introducing hydrogen, pressurizing to 0.8-1.0 MPa, and reacting for 15 hours at room temperature; after completion of the reaction, the palladium on carbon was removed by filtration and washed with methylene chloride (500 ml). The dichloromethane and part of the ethanol were concentrated, cooled to 0-10 ℃ and stirred for 1 hour, filtered and dried at 60 ℃ to constant weight to give 76.3g of a white solid with a yield of 96.1%.
Step four, preparation of FLXT-4
A2000 ml reaction flask was charged with FLXT-3(50g), tetrahydrofuran (350ml) and 0.5mol/l sulfuric acid (950ml), cooled to 0-5 ℃, and a 30% aqueous solution of sodium nitrite (94g) was added dropwise and stirred for 30 minutes after completion of the addition. Dropwise adding 50% potassium iodide aqueous solution (220g) at 0-10 deg.C; after dropping, the reaction was carried out at room temperature for 2 hours. After the reaction, ethyl acetate (600ml) was added and extracted. The organic phase was washed with water 10% aqueous sodium hydrogen sulfite (500ml), saturated aqueous sodium hydrogen carbonate (800ml) and saturated brine (800ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil, slurried with ethanol, filtered and dried to give 54.7g of a beige solid in a yield of 81.1%.
MS(m/z)：299.14[M+H]+
1H NMR(400MHZ，CDCl3，TMS)δ：7.86-7.88(m，3H)，7.61-7.68(m，3H)，7.31-7.35(m，1H)，7.06-7.08(m，1H)，6.85-6.89(m，1H)，3.10-3.30(m，8H).
Step four, preparation of FLXT-4
A2000 ml reaction flask was charged with FLXT-3(50g), tetrahydrofuran (350ml) and 0.5mol/l trifluoroacetic acid (1000ml), cooled to 0 ℃ and added dropwise with a 30% aqueous solution of sodium nitrite (94g), and stirred for 30 minutes after completion of the dropwise addition. Dropwise adding 50% potassium iodide aqueous solution (220g) at 0-10 deg.C; after dropping, the reaction was carried out at room temperature for 2 hours. After the reaction, ethyl acetate (600ml) was added and extracted. The organic phase was washed with water 10% aqueous sodium hydrogen sulfite (500ml), saturated aqueous sodium hydrogen carbonate (800ml) and saturated brine (800ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil, slurried with ethanol, filtered and dried to give 53.4g of a beige solid in a yield of 79.2%.
Step five, preparation of FLXT-5
CuI (5.90g), 2, 4-dimethylthiophenol (20.7g, 0.15mol), KOH (16.8g, 0.3mol), FLXT-4(42.8g, 0.1mol) and dioxane (430ml) were charged into a 1000ml reaction flask, reacted at 95-100 ℃ and heated under reflux for 24 hours. After the reaction is finished, cooling to room temperature, and filtering to remove inorganic salts; dichloromethane (500ml) was added for extraction separation, and the organic phase was washed 3 times with saturated brine (500ml), concentrated to dryness to give an oil, slurried with n-hexane for 1 hour, filtered and dried at 50 ℃ to constant weight to give 38.67g of a pale red solid in 88.2% yield.
Step six, preparation of Thioxetine hydrobromide
To a 30% hydrogen bromide acetic acid solution (137.60g) in a 1000ml reaction flask, 4-methylphenol (16.9g, 0.156mol) was added at room temperature, followed by stirring for 1 hour; FLXT-5(25.0g, 0.057mol) was added and heated to 70-75 ℃ for 2 hours. After the reaction was complete, water (170ml) was slowly added while stirring for 20 minutes. Adding methyl tertiary butyl ether (100ml) and petroleum ether (300ml) and stirring for 2 hours at room temperature; filtering and washing with methyl tertiary butyl ether and water respectively, mixing the obtained wet solid with 110ml of isopropanol, and pulping for 2 hours; filtration and washing with a small amount of isopropanol and drying to constant weight at 50 ℃ gave 18.2g of a white solid in 84.2% yield. HPLC content 99.98%.
Comparative example 1:
reference example 1 (reference CN105017175)
1-acetyl-4- (2- (2, 4-dimethylphenylsulfanyl) phenyl) piperazine (15g, 44.1mmol) and ethanol (100ml) were added to a 250ml reaction flask, dissolved with stirring, and a 15% aqueous sodium hydroxide solution (117.5g) was added; heated to reflux and reacted for 1 hour. After the reaction was complete, the ethanol was concentrated, ethyl acetate (100ml) was added and extracted three times, the organic phase was washed with water (50 ml. times.3) and saturated brine (50 ml. times.3), respectively, and the organic phase was concentrated to give 13.3g (wet weight) of a grayish brown solid.
To the solid obtained by the above concentration was added 170ml of ethyl acetate, and the mixture was dissolved with stirring at room temperature, and a 48% hydrobromic acid solution (7.76g) was added and stirred at room temperature overnight to precipitate a white solid. Filtration and washing with ethyl acetate (30ml) and vacuum drying at 50 ℃ to constant weight gave 7.7g of a white solid in 46.03% yield over the two steps.
Reference example 2 (see WO2017216805)
To a 500ml reaction flask was added 1-benzyl-4- (2- (2, 4-dimethylphenylthio) phenyl) piperazine (6.0g, 15.44mmol) and 1,2 dichloroethane (30ml), dissolved with stirring, and 4A molecular sieves (5gm, 4AMS) were added; 1-chloroethyl chloroformate (5.52g, 38.6mmol) was added dropwise over 10 minutes. After dropping, the mixture was heated to 90 ℃ to react for 3 hours. After the reaction is finished, concentrating the solvent under reduced pressure; cooling to room temperature, adding methanol (20ml), heating to 70 deg.C, and reacting for 2 hr; after the reaction is finished, cooling to room temperature, and concentrating to obtain methanol; adding saturated sodium bicarbonate water solution (100ml) and ethyl acetate (100ml), and extracting; the aqueous phase was extracted with ethyl acetate (100ml), and the organic phases were combined, washed with water and saturated brine, respectively, and dried over anhydrous magnesium sulfate; filtration and concentration gave 2.76g of an off-white solid.
To the solid obtained by the above concentration was added 28ml of ethyl acetate, and the mixture was dissolved with stirring at room temperature, and then 48% hydrobromic acid solution (1.71g) was added and the mixture was stirred at room temperature for 2 hours to precipitate a white solid. Filtration and washing with ethyl acetate (30ml) and drying under vacuum at 50 ℃ to constant weight gave 1.26g of an off-white solid in 21.51% yield in two steps.
Claims (13)
1. A preparation method of vortioxetine hydrobromide is characterized by comprising the following steps:
step 1, reacting o-fluoronitrobenzene and piperazine in an organic solvent at a certain temperature to obtain a compound FLXT-1; the reaction formula is as follows:
step 2, FLXT-1 reacts with methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride and an alkaline compound in an organic solvent at a certain temperature, and a compound FLXT-2 is obtained after post-treatment;
step 3, dissolving the compound FLXT-2 in an organic solvent, and carrying out hydrogenation reduction by using iron powder or palladium carbon as a carrier to obtain FLXT-3;
step 4, dissolving the compound FLXT-3 by using a solvent, adding acid, cooling to-10-5 ℃, dropwise adding a diazotization reagent aqueous solution for reaction, and after the reaction, adding an iodination reagent aqueous solution for reaction to prepare a compound FLXT-4;
step 5, heating a compound FLXT-4, 2,4 dimethyl thiophenol, iodinated ketone and a basic compound in an organic solvent to 80-180 ℃ for reaction, and performing aftertreatment to obtain FLXT-5;
and step 6, mixing the compound FLXT-5 with a phenolic compound and a 30% hydrobromic acid acetic acid solution, reacting at a certain temperature, and performing aftertreatment to obtain high-purity Vortioxetine hydrobromide, wherein the reaction formula is as follows:
wherein in the synthesis process, LG is methylsulfonyl, phenylsulfonyl or p-toluenesulfonyl.
2. The preparation method according to claim 1, wherein in the step 1, the molar ratio of the o-fluoronitrobenzene to the piperazine is 1: 3.0-8.0.
3. The preparation method according to claim 1, wherein in the step 2, the molar ratio of FLXT-1 to methanesulfonyl chloride or benzenesulfonyl chloride or p-toluenesulfonyl chloride, and the basic compound is 1: 1.0-3.0: 1.0 to 3.0; the alkaline compound is triethylamine, pyridine, N-diisopropylethylamine and potassium carbonate; the organic solvent is dichloromethane, toluene and tetrahydrofuran; the certain temperature in the step 2 is 0-40 ℃.
4. The preparation method according to claim 3, wherein the basic compound in the step 2 is triethylamine, the organic solvent is dichloromethane, and the certain temperature is 10-30 ℃.
5. The method according to claim 1, wherein in the step 4, the acid is p-toluenesulfonic acid, sulfuric acid, hydrochloric acid or trifluoroacetic acid; the diazotization reagent is sodium nitrite and potassium nitrite; the iodinating agent is potassium iodide, sodium iodide or methylidene iodide.
6. The method according to claim 5, wherein the diazotizing agent in step 4 is sodium nitrite; the iodinating agent is potassium iodide.
7. The method according to claim 1, wherein in the step 5, the basic compound is sodium carbonate, potassium hydroxide or sodium hydroxide; the organic solvent is selected from one or a combination of any of the following: 1,4 dioxane, N-dimethylformamide or dimethyl sulfoxide; wherein the feeding molar ratio of FLXT-4 to 2, 4-dimethyl thiophenol, iodinated ketone and basic compound is 1.0: 1.1-3.0: 0.02-0.31: 1.5 to 5.0.
8. The method according to claim 7, wherein the basic compound in the step 5 is potassium hydroxide, and the organic solvent is 1,4 dioxane.
9. The method according to claim 1, wherein in step 6, the phenolic compound is p-methylphenol, p-methoxyphenol, phenol or p-diphenol; the certain temperature is 20-90 ℃; the feeding molar ratio of the compound FLXT-5 to the phenolic compound and the hydrobromic acid is 1.0: 1.0-5.0: 3.0 to 20.0.
10. The method according to claim 1, wherein in the step 6, the phenolic compound is p-methylphenol, p-methoxyphenol or phenol.
11. The method according to claim 9, wherein the temperature in step 6 is 50-75 ℃; the feeding molar ratio of the compound FLXT-5 to the phenolic compound and the hydrobromic acid is 1.0: 1.5-3.0: 4.0 to 11.0.
12. The preparation method according to claim 9, wherein the temperature in the step 6 is 60-70 ℃, and the feeding molar ratio of the compound FLXT-5 to the phenolic compound and the hydrobromic acid is 1.0: 1.8-2.5: 5.0 to 8.0.
13. The method according to claim 6, wherein in the step 5, the molar ratio of FLXT-4 to 2, 4-dimethylthiophenol, the iodinated ketone and the basic compound is 1.0: 1.2-1.8: 0.05-0.10: 1.9 to 2.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017175A (en) * | 2014-04-24 | 2015-11-04 | 杭州和泽医药科技有限公司 | Preparation method for vortioxetine |
| WO2015169130A1 (en) * | 2014-05-09 | 2015-11-12 | 上海科胜药物研发有限公司 | New vortioxetine intermediate and synthesis process thereof |
| WO2018014880A1 (en) * | 2016-07-22 | 2018-01-25 | 李勤耕 | Vortioxetine analogue and use and preparation thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017175A (en) * | 2014-04-24 | 2015-11-04 | 杭州和泽医药科技有限公司 | Preparation method for vortioxetine |
| WO2015169130A1 (en) * | 2014-05-09 | 2015-11-12 | 上海科胜药物研发有限公司 | New vortioxetine intermediate and synthesis process thereof |
| WO2018014880A1 (en) * | 2016-07-22 | 2018-01-25 | 李勤耕 | Vortioxetine analogue and use and preparation thereof |
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